Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([I:9])=[CH:4][N:3]=1.C=O.[C:12](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>CC(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH3:12])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Nc1cc(Cl)ncc1I
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CNc1cc(Cl)ncc1I
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 78.1 %

Procedure:
2-Chloro-5-iodopyridin-4-amine (2.0 g, 7.86 mmol) and paraformaldehyde (0.472 g, 15.7 mmol) were dissolved in AcOH (56.1 mL) and stirred for 2.5 hours at 40° C. Sodium triacetoxyborohydride (3.66 g, 17.3 mmol) was added and the mixture was stirred at 40° C. for 1.5 hours. Further sodium triacetoxyborohydride (3.66 g, 17.3 mmol) was added and the mixture was stirred for a further 19 hours. The reaction mixture was reduced in volume by half by evaporation in vacuo. Water was added to the mixture, followed by basification with NaHCO3. The mixture was extracted with EtOAc (3×70 mL) and the combined organic layers were dried over MgSO4. Silica was added and the solution was concentrated. Gradient chromatography, eluting with 5-10% EtOAc in c-Hex for 4 column volume and then 10% EtOAc in c-Hex for a further 11 column volume, gave 2-chloro-5-iodo-N-methylpyridin-4-amine (1.65 g, 6.14 mmol, 78% yield) as a white crystalline powder.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6]C=1)(=O)[CH3:2].[S:9]1[CH:13]=[CH:12][C:11]([C:14]([CH2:16][C:17]#[N:18])=[O:15])=[CH:10]1.C1(=O)CCCC1.N1CCOCC1.[S]>>[NH2:18][C:17]1[S:6][C:7]2[CH2:2][CH2:1][CH2:4][C:8]=2[C:16]=1[C:14]([C:11]1[CH:12]=[CH:13][S:9][CH:10]=1)=[O:15]
Reactant: CC(=O)c1ccsc1
Reactant: N#CCC(=O)c1ccsc1
Agent: [S]
Solvent: O=C1CCCC1
Solvent: C1COCCN1
Product: Nc1sc2c(c1C(=O)c1ccsc1)CCC2
Yield: 71 %

Procedure:
The procedure of Example 1 was followed except that 3-acetylthiophene (Aldrich) was used in place of acetophenone to prepare the corresponding-2-(thiophene-3-carbonyl)acetonitrile (Steps A and B). Cyclopentanone (Aldrich), 2-(thiophene-3-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 71%; IR (KBr) cm−1: 3330, 3117, 2846, 1569, 1448, 1435, 1265, 855, 836, 757, 715; 1H NMR (CDCl3):δ 2.24 (m, 4H), 2.71 (m, 2H), 6.83 (bs, 2H), 7.33 (m, 2H), 7.56 (m, 1H); yellow solid, mp: 125–127° C. (petroleum ether).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][NH:8][C:9]2[N:14]=[C:13]([C@@H:15]([NH:25][C:26](=[O:44])[CH2:27][N:28]3[C:36]4[C:35]([F:38])([F:37])[CH2:34][CH2:33][C:32]([F:40])([F:39])[C:31]=4[C:30]([CH:41]([F:43])[F:42])=[N:29]3)[CH2:16][C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[C:12]([C:45]3[CH:46]=[CH:47][C:48]([F:54])=[C:49]([CH:53]=3)[C:50]([NH2:52])=[O:51])=[CH:11][N:10]=2)[CH:5]=[CH:4]N=N1.[O:55]1CCN(CCN)[CH2:57][CH2:56]1.BrC1C([C@@H](NC(=O)OC(C)(C)C)CC2C=C(F)C=C(F)C=2)=NC(S(C)(=O)=O)=NC=1>>[F:42][CH:41]([F:43])[C:30]1[C:31]2[C:32]([F:40])([F:39])[CH2:33][CH2:34][C:35]([F:38])([F:37])[C:36]=2[N:28]([CH2:27][C:26]([NH:25][C@H:15]([C:13]2[C:12]([C:45]3[CH:46]=[CH:47][C:48]([F:54])=[C:49]([CH:53]=3)[C:50]([NH2:52])=[O:51])=[CH:11][N:10]=[C:9]([NH:8][CH2:7][CH2:6][N:1]3[CH2:5][CH2:4][O:55][CH2:56][CH2:57]3)[N:14]=2)[CH2:16][C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=2)=[O:44])[N:29]=1
Reactant: NCCN1CCOCC1
Reactant: NC(=O)c1cc(-c2cnc(NCCn3ccnn3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)c1nc(S(C)(=O)=O)ncc1Br
Product: NC(=O)c1cc(-c2cnc(NCCN3CCOCC3)nc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)F)c3c2C(F)(F)CCC3(F)F)ccc1F

Procedure:
The title compound (28) was prepared according to the method presented for the synthesis of compound 23F of Example 23 starting with 2-morpholinoethanamine and 23B. 1H NMR (400 MHz, CD3OD) δ 8.76 (d, J=7.8 Hz, 1H), 8.14 (s, 1H), 7.46-7.32 (m, 2H), 7.22 (dd, J=10.7, 8.5 Hz, 1H), 7.00-6.59 (m, 2H), 6.43 (d, J=6.2 Hz, 2H), 5.23 (m, 1H), 5.02 (q, J=16.6 Hz, 2H), 3.97 (m, 6H), 3.70-3.39 (m, 6H), 3.10-2.93 (m, 2H), 2.66-2.38 (m, 4H). MS (m/z) 785.29 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:14][C:15](=[O:29])[C:16]([NH:18][C:19]([CH3:28])([CH3:27])[CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:17])[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][CH:12]=[N:11][CH:10]=1.[CH:30]1([CH:36]=O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(O)(=O)C.ClCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:30]1([CH2:36][N:24]2[CH2:23][CH2:22][N:21]([CH2:20][C:19]([NH:18][C:16](=[O:17])[C:15]([NH:14][C:5]3[CH:6]=[CH:7][C:8]([C:9]4[O:13][CH:12]=[N:11][CH:10]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[O:29])([CH3:27])[CH3:28])[CH2:26][CH2:25]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: COc1cc(NC(=O)C(=O)NC(C)(C)CN2CCNCC2)ccc1-c1cnco1
Reactant: O=CC1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(NC(=O)C(=O)NC(C)(C)CN2CCN(CC3CCCCC3)CC2)ccc1-c1cnco1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred solution of 48 mg of N-[3-methoxy-4-(5-oxazolyl)phenyl]-N′-[1,1-dimethyl-2-(1-piperazinyl)ethyl]oxalamide (1.2 mmol) and 13 mg of cyclohexanecarboxaldehyde (1.2 mmol) in 1 ml of a 5% acetic acid/dichloromethane mixture was treated with a solution of 38 mg of sodium triacetoxyborohydride (1.8 mmol) in 1 ml of a 5% acetic acid/dichloromethane mixture. After stirring overnight at room temperature the reaction mixture was diluted with 10 ml of dichloromethane and washed with 8 ml of a sodium bicarbonate solution followed by 8 ml of water. The organic layer was then evaporated and purified using flash chromatography on a silica gel column eluting with 5% methanol/dichloromethane to give after evaporation of the fractions 14.3 mg (0.3 mmol, 25%) of N-[2-[4-(cyclohexylmethyl)-1-piperazinyl-1,1-dimethylethyl]-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide in the form of a white solid. MS: m/e 498.2 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[C:10]([C:14]#[N:15])[C:11]=2[C:12]#[N:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]Br.C>C(Cl)(Cl)Cl>[Br:16][C:9]1[NH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]#[N:13])[C:10]=1[C:14]#[N:15]
Reactant: N#Cc1c[nH]c(-c2ccccc2)c1C#N
Reactant: BrBr
Agent: C
Solvent: ClC(Cl)Cl
Product: N#Cc1c(Br)[nH]c(-c2ccccc2)c1C#N
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen purge, 2-phenyl-pyrrole-3,4-dicarbonitrile (1.4 g; 0.0075 mol) is added to CHCl3 (35 mL), much of the solid dissolving. A solution of bromine (0.4 mL; 0.008 mol) in CHCl3 (5 mL) is added dropwise over 20 minutes. Initially the color is discharged rapidly, but as a new, gummy solid begins to precipitate, the color remains. After stirring 30 minutes at ambient, the mixture is brought to reflux, resulting in a much more discreet solid. After refluxing 90 minutes, the reaction mixture is cooled and an aliquot is removed and analyzed (HPLC), showing ca. 60% starting material still remaining. In a single portion fresh bromine (0.2 mL; 0.004 mol) is added, and refluxing continued another 45 minutes whereupon an aliquot shows 10% starting material remaining. Another fresh portion of bromine (0.2 mL; 0.004 mol) is added to the refluxing suspension and refluxing is continued another 30 minutes. The suspension is cooled and stirred 18 hours at room temperature. Solvent is removed under reduced pressure to yield a greenish solid which is extracted with hot CHCl3, leaving behind a dark residue. The extract is treated with DARCO and filtered hot. The clear yellow filtrate quickly began to deposit a white precipitate. After cooling to -10° C., the white solid is collected by filtration.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[N:7]([CH2:16][C:17]1[CH:18]=[N:19]C(C=O)=[C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=2)[C:22]=1[CH3:23])[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C-:37]#N.[Na+].[C:40]([OH:43])(=[O:42])[CH3:41]>CO.[O-2].[O-2].[Mn+4]>[CH3:37][O:42][C:40]([C:41]1[C:21]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[N:33])[CH:27]=2)=[C:22]([CH3:23])[C:17]([CH2:16][N:7]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:36])[C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][CH:13]=2)=[CH:18][N:19]=1)=[O:43]
Reactant: CC(=O)O
Reactant: Cc1c(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)cnc(C=O)c1OCc1cccc(C#N)c1
Reactant: [C-]#N
Agent: [Mn+4]
Agent: [Na+]
Agent: [O-2]
Solvent: CO
Product: COC(=O)c1ncc(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)c(C)c1OCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.3 %

Procedure:
A mixture of [5-(3-cyano-benzyloxy)-6-formyl-4-methyl-pyridin-3-ylmethyl]-(4-cyano-phenyl)-carbamic acid tert-butyl ester (141) (140 mg, 0.3 mmol), sodium cyanide (272 mg, 5.5 mmol), manganese (IV) dioxide (422 mg, 85%, 0.29 mmol), acetic acid (256 mg, 4.2 mmol) in methyl alcohol (40 mL) was stirred at room temperature for 12 hours. The solid was filtered through a celite pad and washed several times with methanol. The filtrate was evaporated to give a crude residue, which was purified by column chromatography on silica gel using a gradient mixture of ethyl acetate:hexane (0:1 to 1:0) as eluant to give 5-{[tert-butoxycarbonyl-(4-cyano-phenyl)-amino]-methyl}-3-(3-cyano-benzyloxy)-4-methyl-pyridine-2-carboxylic acid methyl ester (143) (142 mg, 96% yield) as a light yellow oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[C@@:40]2([CH3:41])[C:12](=[CH:13][CH2:14][C@@H:15]3[C@@H:39]2[CH2:38][CH2:37][C@@:36]2([CH3:42])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[C@H:20]([CH2:34][OH:35])[CH2:21][CH2:22][C@H:23]([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])[CH2:11][C@@H:10]([O:43][CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][O:45]2)[CH2:9]1.[C:50]1([CH3:60])[CH:55]=[CH:54][C:53]([S:56](Cl)(=[O:58])=[O:57])=[CH:52][CH:51]=1>N1C=CC=CC=1>[CH3:60][C:50]1[CH:55]=[CH:54][C:53]([S:56]([O:35][CH2:34][C@@H:20]([C@@H:19]2[C@:36]3([CH3:42])[C@H:16]([C@H:15]4[C@H:39]([CH2:38][CH2:37]3)[C@:40]3([CH3:41])[C:12]([CH2:11][C@@H:10]([O:43][CH:44]5[CH2:49][CH2:48][CH2:47][CH2:46][O:45]5)[CH2:9][C@@H:8]3[O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)=[CH:13][CH2:14]4)[CH2:17][CH2:18]2)[CH2:21][CH2:22][C@H:23]([F:33])[C:24]([O:27][CH:28]([O:30][CH2:31][CH3:32])[CH3:29])([CH3:26])[CH3:25])(=[O:58])=[O:57])=[CH:52][CH:51]=1
Reactant: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](CO)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOC(C)OC(C)(C)[C@@H](F)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 0.19 g. (0.00027 mole) of [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol, 1 ml. of pyridine and 0.104 g. (0.00054 mole) of p-toluenesulfonyl chloride was stirred at 0° C. for 18 hr. The mixture was quenched with ice chips. The mixture was then poured into water and extracted with methylene chloride. The organic phase was washed with 10% aqueous sulfuric acid and saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to yield oily [1α,3β,24S]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol 21-(4-methylbenzenesulfonate).
Reaction SMILES: [C:1](=[S:3])=[S:2].[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH3:13])[N:6]=1.[CH2:14](OCC)[CH3:15]>C(#N)C.C(N(CC)CC)C>[CH2:11]([C:7]1[N:6]=[C:5]([NH:4][C:1](=[S:3])[S-:2])[CH:10]=[CH:9][CH:8]=1)[CH2:12][CH3:13].[CH2:14]([NH+:6]([CH2:5][CH3:10])[CH2:7][CH3:11])[CH3:15]
Reactant: S=C=S
Reactant: CCCc1cccc(N)n1
Reactant: CCOCC
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCc1cccc(NC(=S)[S-])n1
Product: CC[NH+](CC)CC
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A solution of carbon disulphide (20 cc) in anhydrous acetonitrile (23 cc) is added, at 20° C., to a solution of 2-amino-6-propylpyridine (34.0 g) in anhydrous triethylamine (69 cc). After stirring of the mixture for 20 hours at 20° C., anhydrous diethyl ether (800 cc) is added. After cooling for 1 hour at 2° C., the resulting crystals are filtered off, washed three times with anhydrous diethyl ether (total 300 cc) and dried under reduced pressure (20 mm Hg) at 20° C. Triethylammonium 6-propylpyrid-2-yldithiocarbamate (50.3 g), melting at about 98° C., is obtained.
Reaction SMILES: C[O:2][C:3](=O)[NH2:4].[Cl:6][C:7]1[C:8]([F:16])=[C:9]([CH2:13][CH2:14]N)[CH:10]=[CH:11][CH:12]=1>O>[Cl:6][C:7]1[C:8]([F:16])=[C:9]2[C:10](=[CH:11][CH:12]=1)[C:3](=[O:2])[NH:4][CH2:14][CH2:13]2
Reactant: COC(N)=O
Reactant: NCCc1cccc(Cl)c1F
Solvent: O
Product: O=C1NCCc2c1ccc(Cl)c2F
Temperature: 150 °C
Yield: 3.9 %

Procedure:
[2-(3-Chloro-2-fluoro-phenyl)-ethylamine]-carbamic methyl ester (890 mg, 3.85 mmol) and polyphosphoric acid (15 mL) were added to a 1-L, round bottom flask equipped with a magnetic stirring bar and reflux condenser. The reaction mixture was heated in an oil bath at 140-160° C. for 2 hours while keeping vigorous stirring. The reaction mixture was then allowed to cool to room temperature and poured into H2O (100 mL). After extraction with EtOAc, the organic layer was washed with brine, dried over anhy. MgSO4, filtered and concentrated to give a yellowish oil which was crystallized from Et2O to give title compound as a white solid (30 mg, 4%). MS: 200.1 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:33](=[O:49])[NH:34][CH2:35][CH2:36][N:37](C(OCC1C=CC=CC=1)=O)[CH3:38])[CH2:9][CH2:10][CH2:11][NH:12]/[C:13](/[NH2:32])=[N:14]/[S:15]([C:18]1[C:19]([CH3:31])=[C:20]([CH3:30])[C:21]2[O:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]=2[C:28]=1[CH3:29])(=[O:17])=[O:16])(C)(C)C.CC(O)=O>CO.O.[Pd]>[CH3:38][NH:37][CH2:36][CH2:35][NH:34][C:33](=[O:49])[C@@H:8]([NH2:7])[CH2:9][CH2:10][CH2:11][NH:12]/[C:13](/[NH2:32])=[N:14]/[S:15]([C:18]1[C:19]([CH3:31])=[C:20]([CH3:30])[C:21]2[O:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]=2[C:28]=1[CH3:29])(=[O:17])=[O:16]
Reactant: Cc1c(C)c(S(=O)(=O)/N=C(\N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCN(C)C(=O)OCc2ccccc2)c(C)c2c1OC(C)(C)C2
Agent: [Pd]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CNCCNC(=O)[C@@H](N)CCCN/C(N)=N/S(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2
Reaction time: 2.5 h
Yield: 55.5 %

Procedure:
Compound D (4.14 g, 5.77 mmol) and AcOH (330 μl, 5.77 mmol) was dissolved in methanol (40 ml) followed by the addition of Pd/C (5% wt, 880 mg) suspension in water (5 ml). The reaction mixture was subjected to hydrogenation (Parr apparatus, 75 psi) at room temperature for 2.5 h. The catalyst was filtered over a pad of Celite on sintered glass funnel and washed with methanol. Filtrate was evaporated in vacuo to provide compound E (1.96 g, 3.2 mmol) as yellowish amorphous solid. LC-MS [M+H] 483.2 (C22H38N6O4S+H, calc: 483.2).
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-:5]C(C)C)C.[F:9][C:10]([F:17])([F:16])[C:11]([O:13]CC)=O.C(#N)C>C1COCC1>[F:17][C:10]([F:9])([F:16])[C:11](=[O:13])[CH2:2][C:3]#[N:5]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: N#CCC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 56.7 %

Procedure:
To a cooled (−78° C.) solution of LDA (2M, 15 g, 39 mmol) in anhydrous THF (50 mL) was added drop-wise a solution of ethyl trifluoroacetate (2.5 g, 18 mmol) and acetonitrile (1.4 g, 35 mmol) in 15 ml THF. The reaction was kept at −78° C. for 45 min, warmed up to room temperature over 1 hour period and quenched with ice water. The reaction was concentrated under vacuum, the residue extracted with ethyl ether, the pH brought to 1 with concentrated HCl, extracted with dichloromethane. The aqueous solution was extracted with ethyl ether, the combined organic layers dried over anhydrous sodium sulfate, and the solvent was removed under vacuum to afford 1.4 g of 4,4,4-trifluoro-3-oxobutanenitrile as a yellow oil, which was used as such in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]#[N:13])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[H][H]>[Pd].CO>[ClH:1].[NH2:13][CH2:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1
Reactant: [H][H]
Reactant: N#Cc1ncc(C(F)(F)F)cc1Cl
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ncc(C(F)(F)F)cc1Cl
Reaction time: 4 h
Yield: 95 %

Procedure:
A mixture of 3-chloro-2-cyano-5-trifluoromethylpyridine (5.1 g) and 5% palladium on charcoal (5.1 mg as Pd metal) was stirred at 20° C. with methanol and concentrated hydrochloric acid (2.5 ml) under 1 atmosphere of hydrogen. After 4 hours the reaction was judged to be complete by hplc. The mixture was filtered through Celatom, washed with methanol and water and evaporated to give 2-aminomethyl-3-chloro-5-trifluoromethylpyridine hydrochloride in 95-97% yield, NMR (in D2O) 4.6 (s, 2H), 8.35 (s, 1H), 8.9 (s, 1H).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[C:10]([O:20][CH3:21])=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15].ClC(OCC)=O.[NH2:28][CH:29]1[CH2:33][N:32]([CH2:34][CH3:35])[N:31]([CH2:36][CH3:37])[CH2:30]1>C(Cl)Cl>[OH2:15].[Br:8][C:9]1[C:10]([O:20][CH3:21])=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=1)[C:14]([NH:28][CH:29]1[CH2:33][N:32]([CH2:34][CH3:35])[N:31]([CH2:36][CH3:37])[CH2:30]1)=[O:16].[Br:8][C:9]1[C:10]([O:20][CH3:21])=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=1)[C:14]([NH:28][CH:29]1[CH2:33][N:32]([CH2:34][CH3:35])[N:31]([CH2:36][CH3:37])[CH2:30]1)=[O:16]
Reactant: COc1cc(OC)c(C(=O)O)cc1Br
Reactant: CCN1CC(N)CN1CC
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CC(NC(=O)c2cc(Br)c(OC)cc2OC)CN1CC
Product: O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.2 %

Procedure:
A solution of triethylamine (1.52 g, 0.0150 mole) in 5 ml methylene chloride was added to a stirred solution of 5-bromo-2,4-dimethoxybenzoic acid (3.92 g, 0.0150 mole) in 75 ml of methylene chloride. After stirring for 20 minutes at room temperature, the mixture was cooled to 0° C. with an ice water bath. A solution of ethyl chloroformate (1.63 g, 0.0150 mole) in 10 ml methylene chloride was added dropwise to the cold stirred reaction mixture, and the mixture stirred at 0° C. for 30 minutes. Then a solution of 4-amino-1,2-diethylpyrazolidine (2.15 g, 0.0150 mole) in 10 ml of methylene chloride was added dropwise to the cold reaction mixture. The mixture was stirred for 30 minutes at 0° C. and then allowed to warm to room temperature and stirred for 16 hr. The mixture was concentrated to a semi-solid residue which was triturated in 10 ml methanol and 20 ml of a saturated aqueous sodium bicarbonate solution. The mixture was extracted with 2×75 ml portions of methylene chloride, the extract dried (magnesium sulfate) and concentrated to give a solid. The solid was triturated with isopropyl ether and filtered to give 4.28 g (73.9%) of cream-colored solid; recrystallization from isopropyl ether gave 2.04 g of the product; m.p. 113.5°-114.5° C. NMR analysis showed the solid to be a monohydrate, vacuum drying at 54° C. for 16 hrs gave the hemihydrate, m.p. 114°-115° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(N(C(C)C)CC)(C)C.[C:25]1([CH3:34])[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([NH:1][C:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:34])=[CH:26][CH:27]=2)=[O:32])[CH:11]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:8]
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(NC(=O)c2ccc(C)cc2)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To 1.20 g (5.74 mmol) of methyl 5-amino-3-(methoxycarbonyl)benzoate, compound 87, suspended in 50 mL of chloroform and 1.05 mL (6.00 mmol) of diisopropylethylamine was added 836 μL (6.32 mmol) of p-toluoyl chloride in 10 mL of chloroform over 30 min. The reaction was allowed to stir at ambient temperature for 2 hr. Then, another 100 μL (0.60 mmol) of diisopropylethylamine and 100 μL (0.76 mmol) of p-toluoyl chloride in 2 mL of chloroform was added. After an addition 30 min, the volatiles were removed by rotary evaporation and the resulting residue was dissolved in ethyl acetate and extracted with 0.1 N aqueous NaOH followed by extraction with water. The organic layer was dried (MgSO4), filtered, and volatiles removed in vacuo. This provided 1.86 g (5.68 mmol) of the desired compound. The product was identified by 1H NMR and mass spectroscopy and purity was assessed by RP-HPLC.
Reaction SMILES: C1C[O:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[C:12]([NH:15][C:16]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]2[C:17]=1[C:18](=[O:27])[CH2:19][CH2:20][S:21]2)(=[O:14])[CH3:13].[N:28](OCCCC)=O>CCOCC>[C:3]([NH:28][CH:19]1[C:18](=[O:27])[C:17]2[C:22](=[C:23]([CH3:26])[CH:24]=[CH:25][C:16]=2[NH:15][C:12](=[O:14])[CH3:13])[S:21][CH2:20]1)(=[O:4])[CH3:2]
Reactant: CC(=O)Nc1ccc(C)c2c1C(=O)CCS2
Reactant: CCCCON=O
Reactant: C1CCOC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: CC(=O)Nc1ccc(C)c2c1C(=O)C(NC(C)=O)CS2
Reaction time: 0.08 h

Procedure:
To 3 ml of a THF solution containing 153 mg of potassium-t-butoxide was added 9 ml of a THF solution containing 291 mg of 5-acetylamino-8-methyl-4-thiochromanone [J. Heterocyclic Chem., 11, 515 (1974)]. After stirring for 5 minutes, 0.22 ml of n-butyl nitrite was added to the mixture, followed by further stirring for 1 hour at room temperature. After the addition of 20 ml of ether, the reaction mixture was stirred for another 1 hour. The deposited precipitate was collected by filtration, washed thoroughly with ether, and dissolved into a mixture of 20 ml of acetic acid and 20 ml of acetic anhydride. To the solution was added about 200 mg of zinc powder at room temperature while stirring. After the addition, the stirring was continued for a further 0.5 hour. Insoluble substances were removed by filtration, the solvent was evaporated, and 20 ml of chloroform was added to the residue. The residue, after washing with water, saturated aqueous solution of sodium hydroxide, and saturated brine in this order, was dried over anhydrous sodium sulfate. After evaporating the solvent, the residue was subjected to silica gel column chromatography using a hexane-ethyl acetate (4:1) mixed solvent as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 109 mg of the title compound.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([F:23])=[C:17]([CH2:19][C:20](Cl)=[O:21])[CH:18]=1>C(OCC)(=O)C>[CH2:1]([O:4][C:20](=[O:21])[CH2:19][C:17]1[CH:18]=[C:13]([Br:12])[CH:14]=[CH:15][C:16]=1[F:23])[CH:2]=[CH2:3]
Reactant: O=C(Cl)Cc1cc(Br)ccc1F
Reactant: C=CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCOC(=O)Cc1cc(Br)ccc1F
Reaction time: 1 h

Procedure:
To a mixture of allyl alcohol (22.1 g, 380.5 mmol) and triethylamine (Et3N) (5.4 ml, 39 mmol) at 0° C. was added over 1 h crude (5-bromo-2-fluoro-phenyl) -acetyl chloride (intermediate B2A) (7.01 g, ca. 26 mmol). Then the reaction was stirred over 1 h from 0° C. to 23° C. The reaction mixture was diluted with ethyl acetate, washed with water, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuum left the title compound as a yellow oil (7.290 g, 103%), which was used without further purification. MS (ISP): m/z=280.1 [(M+NH4)+] and 282.1 [(M+2+NH4)+]